Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies

Cell Metab. 2018 Dec 4;28(6):848-865.e6. doi: 10.1016/j.cmet.2018.08.006. Epub 2018 Aug 30.


The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional or pharmacological targeting of molecules involved in the lactate axis abrogated in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This adaptive resistance mechanism was observed in lung cancer patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance.

Keywords: CAFs; EGFR; HGF/MET; LDH; MCT1/4; lactate; resistance; targeted therapy; tumor metabolism; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cancer-Associated Fibroblasts / drug effects
  • Cancer-Associated Fibroblasts / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism
  • Glycolysis / drug effects*
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Lactic Acid / metabolism*
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / metabolism
  • Mice, Inbred NOD
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism
  • Tumor Microenvironment / drug effects*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Lactic Acid
  • Hepatocyte Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met